Coronavirus COVID-19 Update for April 11, 2021

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Clinical Reports

Ivermectin for Treatment of Mild-to-Moderate COVID-19 in the Outpatient Setting: A Decentralized, Placebo-controlled, Randomized, Platform Clinical Trial
Study authors evaluated the efficacy of ivermectin 400 mcg/kg daily for 3 days compared with placebo for the treatment of early mild-to-moderate COVID-19. ACTIV-6 is an ongoing, decentralized, double-blind, randomized, placebo-controlled platform trial to evaluate repurposed therapies in outpatients with mild-to-moderate COVID-19. Non-hospitalized adults age >=30 years with confirmed COVID-19, experiencing 2 or more symptoms of acute infection for <=7 days were randomized to receive ivermectin 400 mcg/kg daily for 3 days or placebo. The main outcome measure was time to sustained recovery, defined as achieving at least 3 consecutive days without symptoms. Secondary outcomes included a composite of hospitalization or death by day 28. Results: Of the 3457 participants who consented to be evaluated for inclusion in the ivermectin arm, 1591 were eligible for this study arm, randomized to receive ivermectin 400 mcg/kg (n=817) or placebo (n=774), and received study drug. Of those enrolled, 47% reported receiving at least 2 doses of SARS-CoV-2 vaccination. The posterior probability for any improvement in time to recovery was 0.91 (hazard ratio 1.07, 95% credible interval 0.96 to 1.17). The posterior probability of this benefit exceeding 24 hours was less than 0.01, as measured by the difference in mean time unwell. Hospitalizations or deaths were uncommon (ivermectin [n=10]; placebo [n=9]). Ivermectin at 400 mcg/kg was safe and without serious adverse events as compared with placebo (ivermectin [n=10]; placebo [n=9]). Ivermectin dosed at 400 mcg/kg daily for 3 days resulted in less than one day of shortening of symptoms and did not lower incidence of hospitalization or death among outpatients with COVID-19 in the United States during the delta and omicron variant time periods.
Persistence of residual SARS-CoV-2 viral antigen and RNA in tissues of patients with long COVID-19
The World Health Organization has defined long COVID-19 (LC) as a condition where patients exhibit persistent symptoms over time after its acute phase, which cannot be explained by alternative diagnosis. Since researchers have previously reported residual viral antigens in tissues of convalescent patients, they now aim to assess the presence of such antigens in post-convalescent tissues. Here, they established the presence of residual virus within the appendix and breast tissue of 2 patients who exhibited LC symptoms, 175 to 462 days upon positive diagnosis, using immunohistological techniques. They observed positive staining for viral nucleocapsid protein (NP) in the appendix, and tumour-adjacent region of the breast, but not within the tumour via multiplex immunohistochemistry. Notably, with RNAscope, both positive-sense and negative-sense (replicative intermediate) viral RNA were detected. As a single-stranded virus, SARS-CoV-2, have to produce a replicative intermediate as a template to synthesize new genomic RNAs. Thus, the detection of negative-sense viral RNA suggests ongoing viral replication. While viral RNA and antigen from gastrointestinal and stool samples of convalescent patients has been extensively reported, researchers believe this is the first study to detect viable virus. Furthermore, this positive finding in the breast tissue also corroborated with recent reports that immunocompromised patients had also experienced LC symptoms and persistent viral replication. Overall, these findings, along with emerging LC studies, raises the possibility of the gastrointestinal tract functioning as a reservoir.

Antiviral Therapeutics and Vaccines

Intramuscular AZD7442 (Tixagevimab–Cilgavimab) for Prevention of Covid-19
Pharmacokinetic data in humans indicate that AZD7442 has an extended half-life of approximately 90 days. These are results from an ongoing phase 3 trial, that enrolled adults (≥18 years of age) who had an increased risk of an inadequate response to vaccination against coronavirus disease 2019 (Covid-19), an increased risk of exposure to SARS-CoV-2, or both. Participants were randomly assigned in a 2:1 ratio to receive a single dose (two consecutive intramuscular injections, one containing tixagevimab and the other containing cilgavimab) of either 300 mg of AZD7442 or saline placebo, and they were followed for up to 183 days in the primary analysis. The primary safety end point was the incidence of adverse events after a single dose of AZD7442. The primary efficacy end point was symptomatic Covid-19 (SARS-CoV-2 infection confirmed by means of reverse-transcriptase–polymerase-chain-reaction assay) occurring after administration of AZD7442 or placebo and on or before day 183. A total of 5197 participants underwent randomization and received one dose of AZD7442 or placebo (3460 in the AZD7442 group and 1737 in the placebo group). The primary analysis was conducted after 30% of the participants had become aware of their randomized assignment. In total, 1221 of 3461 participants (35.3%) in the AZD7442 group and 593 of 1736 participants (34.2%) in the placebo group reported having at least one adverse event, most of which were mild or moderate in severity. Symptomatic Covid-19 occurred in (0.2%) in the AZD7442 group and (1.0%) in the placebo group (relative risk reduction, 76.7%; 95% confidence interval [CI], 46.0 to 90.0; P<0.001); extended follow-up at a median of 6 months showed a relative risk reduction of 82.8% (95% CI, 65.8 to 91.4). Five cases of severe or critical Covid-19 and two Covid-19–related deaths occurred, all in the placebo group.
Rebound Phenomenon after Nirmatrelvir/Ritonavir Treatment of Coronavirus Disease-2019 in High-Risk Persons
In a cohort of 483 high-risk patients treated with nirmatrelvir/ritonavir for coronavirus disease-2019, two patients (0.4%) required hospitalization by day 30. Four patients (0.8%) experienced rebound of symptoms, which were generally mild, at median of 9 days after treatment, and all resolved without additional COVID-19-directed therapy.
The anti-SARS-CoV-2 monoclonal antibody, bamlanivimab, minimally impacts the endogenous immune response to COVID-19 vaccination
This longitudinal serological study evaluated the magnitude and potency of the endogenous antibody response to COVID-19 vaccination in participants who first received a COVID-19 monoclonal antibody in a prevention study. Participants received the first COVID-19 vaccine dose at different timepoints (ranging from 43 to 127 days, median 67 days) following bamlanivimab or placebo infusion. The majority did not wait the 90 days suggested previously before starting their vaccination series. All bamlanivimab and placebo recipients mounted a robust immune response to full COVID-19 vaccination, irrespective of age, risk-category, and vaccine type. These findings are pertinent for informing public health policy with results that suggest that the benefit of receiving COVID-19 vaccination at the earliest opportunity outweighs the minimal effect on the endogenous immune response due to prior prophylactic COVID-19 monoclonal antibody infusion.
Combination Therapy With Casirivimab/Imdevimab and Remdesivir for Protracted SARS-CoV-2 Infection in B-cell-Depleted Patients
Profoundly B-cell-depleted patients can have prolonged severe acute respiratory syndrome coronavirus 2 infections with evidence of active viral replication, due to inability to mount an adequate humoral response to clear the virus. In this study, researchers present 3 B-cell-depleted patients with prolonged coronavirus disease 2019 infection who were successfully treated with a combination of casirivimab/imdevimab and remdesivir.

Epidemiology

In-Hospital Mortality Among Hospitalized COVID-19 Patients in the United States: How did it change in 2021?
In this retrospective observational study in US national sample of 501,671 adults hospitalized with COVID-19, adjusted in-hospital mortality decreased from 12% in February 2021 to 9% in April 2021. However, adjusted in-hospital mortality increased to 16% in September and October 2021. Adjusted ICU admission fluctuated between 20-27% in 2021.
Rheumatic Symptoms Following Coronavirus Disease 2019 (COVID-19): A Chronic Post–COVID-19 Condition
In this prospective, longitudinal cohort study, discharged patients with COVID-19 were interviewed face-to-face at 12 months after symptom onset. Rheumatic symptoms following COVID-19 included newly occurring joint pain and/or joint swelling. The risk factors of developing rheumatic symptoms were identified by multivariable logistic regression analysis. In total, 1296 of 2469 discharged patients with COVID-19 were enrolled in this study. Among them, 160 (12.3% [95% confidence interval {CI}, 10.6%–14.3%]) suffered from rheumatic symptoms following COVID-19 at 12-month follow-up. The most frequently involved joints were the knee joints (38%), followed by hand (25%) and shoulder (19%). Rheumatic symptoms were independent of the severity of illness and corticosteroid treatment during the acute phase, while elderly age (odds ratio [OR], 1.22 [95% CI, 1.06–1.40]) and female sex (OR, 1.58 [95% CI, 1.12–2.23]) were identified as the risk factors for this condition. This investigation showed a considerable proportion of rheumatic symptoms following COVID-19 in discharged patients, which highlights the need for continuing attention. Notably, rheumatic symptoms following COVID-19 were independent of the severity of illness and corticosteroid treatment during the acute phase.